title: RNA processing is altered in skeletal muscle nuclei of patients affected by myotonic dystrophy.
abstract: Myotonic dystrophies (DMs) are characterised by highly variable clinical manifestations consisting of muscle weakness and atrophy, and a wide spectrum of extramuscular manifestations. In both DM1 and DM2 forms, expanded nucleotide sequences cause the accumulation of mutant transcripts in the nucleus, thus deregulating the function of some RNA-binding proteins and providing a plausible explanation for the multifactorial phenotype of DM patients. However, at the skeletal muscle level, no mechanistic explanation for the muscle wasting has so far been proposed. We therefore performed a study in situ by immunoelectron microscopy on biceps brachii biopsies from DM1, DM2 and healthy subjects, providing the first ultrastructural evidence on the distribution of some nuclear ribonucleoprotein (RNP)-containing structures and molecular factors involved in pre-mRNA transcription and maturation in dystrophic myonuclei. Our results demonstrated an accumulation of splicing and cleavage factors in myonuclei of both DM1 and DM2 patients, suggesting an impairment of post-transcriptional pre-mRNA pathways. The transcription of the expanded sequences in DM myonuclei would therefore hamper functionality of the whole splicing machinery, slowing down the intranuclear molecular trafficking; this would reduce the capability of myonuclei to respond to anabolic stimuli thus contributing to muscle wasting.
authors.affiliation: Dipartimento di Scienze Neurologiche, Neuropsicologiche, Morfologiche e Motorie, Sezione di Anatomia e Istologia, Università di Verona, Verona, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Malatesta
authors.forename: Marzia
authors.initials: M
authors.lastname: Giagnacovo
authors.forename: Rosanna
authors.initials: R
authors.lastname: Cardani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meola
authors.forename: Carlo
authors.initials: C
authors.lastname: Pellicciari
mesh_terms: D000293:Adolescent; D000328:Adult; D002467:Cell Nucleus / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D012333:RNA, Messenger